Immune system has a skillful surveillance function to distinguish abnormal cells from autochtonous normal cells in the body and eliminate only the abnormal cells. When the surveillance function collapses, abnormal cells produced by mutation and the like cannot be eliminated, and the presence and growth thereof in the body are allowed. The grown abnormal cell mass is a tumor, or cancer.
The cancer treatment is mainly removal of cancer by surgical operation, or use of anti-cancer agents. However, these treatment methods often place physical burden due to extirpative surgery and side effects of anti-cancer agents, or mental burden due to operative scar on patients.
With such background, treatments by immunotherapy are drawing attention. In the immunotherapy, the number of the patients' own immunocytes is increased, and further activated to attack the cancer cells. As compared to surgical operation, physical burden on the patients due to the treatment is small, and an influence on the patients' social life due to the treatment can be minimized. In addition, a treatment method using immunotherapy and a surgical operation in combination is also employed. Since a tumor minimized by immunotherapy is removed, the physical burden on patients can be reduced. Also, since the operative scar is small, the mental burden can also be drastically reduced.
Natural killer (NK) T cells are immune cells belonging to a new lymphocyte lineage that exhibit characteristics different from those of other lymphocyte lineages (T, B, and NK cells). NKT cells are related to NK cells because cytotoxic perforin granules are present therein (non-patent document 1). However, because NKT cells express not only NK cell markers, but also T cell receptors (TCRs), they have been shown to represent a new class of cells that are distinct from known cells (non-patent document 2). NKT cells can produce both Th1 type cytokine [mainly interferon (IFN)-γ] produced by T helper (Th)1 cell that promotes immunostimulatory action, and Th2 type cytokine [mainly interleukin (IL)-4] produced by Th2 cell that promotes immunosuppressive action (non-patent document 3). In other words, NKT cells can induce both activation and quieting of the immune system, which suggests the possible role of the immune system in the balance adjustment (non-patent document 4). Therefore, it is possible to adjust the collapsed balance of the immune system by controlling the function of NKT cells, which enforces the surveillance function to treat cancer.
The characteristic of NKT cells that is attracting the greatest attention resides in the fact that the α chain of TCR expressed in NKT cells is the same in all the individuals belonging to one certain species. This essentially shows that all NKT cells of the same species of organism are activated by the same substance. As such, the α chain is Vα24 for humans and Vα14 for murine animals, there is a very high homology between the two species. For the β chain, which forms a pair with the α chain, only a very limited number of kinds are known, so this TCR is called “invariant TCR”. It is also characteristic that TCR of T cells recognizes a protein fragment, whereas TCR of NKT cells recognizes glycolipid.
A wide variety of sphingoglycolipids are known to exist in living organisms. In general sphingoglycolipids in the living organisms, various sugars or sugar chains are bound to ceramides via β-bonds, and they are present in the cell membranes of various organs (non-patent document 5).
Meanwhile, it is known that sphingoglycolipids comprising sugars bound to ceramides via α-bonds possesses potent immunostimulatory action and antitumor activity (non-patent document 6). α-Galactosylceramides, typified by agelasphins, are glycolipids isolated from extracts from Agelas mauritianus, a kind of marine sponge, and have been reported to potently activate NKT cells (non-patent document 7). α-Galactosyl ceramides are taken by antigen presenting cells (APC) represented by dendritic cell (DC) and the like, and presented on a cellular membrane by CD1d protein similar to major histocompatibility complex (MHC) class I molecule. NKT cells are activated by recognizing a complex of the thus-presented CD1d protein and α-galactosylceramide by using TCR, whereby various immune reactions are initiated.
Heretofore, various analogs have been synthesized, and the correlation between the structure and the activity has been researched. It has been clarified that, among the series of synthetized analogs, KRN7000 (compound 1, α-GalCer) developed by Kirin Brewery Co., Ltd. shows the strongest activity, and the corresponding β-form (β-GalCer) does not show an immunostimulatory activity. KRN7000 is sphingoglycolipid comprising a ceramide resulting from the acylation of the sphingosine base by a long-chain fatty acid, and galactose bound thereto in α-configuration (patent document 1, non-patent document 8).
